Dopamine and agonists and antagonists thereof for modulation of suppressive activity of CD4+CD25+ regulatory T cells

Abstract

Compositions and methods for modulation of the suppressive activity of CD4+CD25+regulatory T cells (Treg) on CD4+CD25− effector T cells (Teff) are provided. An agent selected from: (i) dopamine; (ii) a dopamine precursor; (iii) a D1-R agonist; (iv) a D2-R antagonist; (v) a combination of (i) and (ii); or (vi) a combination of (i), (ii) or (iii) with (iv), down-regulates the suppressive activity of Treg and is useful for treatment of cancer. An agent selected from (i) a dopamine D2-R agonist, (ii) a dopamine D1-R antagonist, and (iii) a combination of (i) and (ii), up-regulates the suppressive activity of Treg and is useful for treatment of an autoimmune disease or for controlling graft rejection in tissue/organ transplantation.

1 . A method for modulating the suppressive effect of CD4 + CD25 +  regulatory T cells (Treg) on CD4 + CD25 −  effector T cells (Teff), which comprises administering to an individual in need an agent selected from the group consisting of dopamine, a dopamine precursor, a dopamine agonist, a dopamine antagonist, and a combination thereof. 
     
     
         2 . A method according to  claim 1  for down-regulating the suppressive effect of Treg on Teff, said method comprising administering to an individual in need an agent that down-regulates the suppressive activity of Treg on Teff, wherein said agent is selected from the group consisting of:
 (i) dopamine or a pharmaceutically acceptable salt thereof;   (ii) a dopamine precursor or a pharmaceutically acceptable salt thereof;   (iii) an agonist of the dopamine receptor type 1 family (D1-R agonist) or a pharmaceutically acceptable salt thereof;   (iv) an antagonist of the dopamine receptor type 2 family (D2-R antagonist) or a pharmaceutically acceptable salt thereof;   (v) a combination of (i) and (ii); and   (vi) a combination of (i), (ii) or (iii) with (iv);   provided that said individual is need is not being treated for a neurodegenerative condition, disorder or disease.   
     
     
         3 . A method according to  claim 2 , wherein said agent is dopamine or a pharmaceutically acceptable salt thereof. 
     
     
         4 . A method according to  claim 2 , wherein said agent is a combination of dopamine and the dopamine precursor levodopa, optionally in further combination with carbidopa. 
     
     
         5 . A method according to  claim 2 , wherein said agent is a dopamine D1-R agonist. 
     
     
         6 . The method according to  claim 5 , wherein said dopamine D1-R agonist is selected from the group consisting of A-77636, SKF-38393, SKF-77434, SKF-81297, SKF-82958, dihydrexidine and fenoldopam. 
     
     
         7 . A method according to  claim 2 , wherein said agent is a dopamine D2-R antagonist. 
     
     
         8 . The method according to  claim 7 , wherein said dopamine D2-R antagonist is selected from the group consisting of amisulpride, clozapine, domperidone, eticlopride, haloperidol, iloperidone, mazapertine, olanzapine, raclopride, remoxipride, risperidone, sertindole, spiperone, spiroperidol, sulpride, tropapride, zetidoline, CP-96345, LU111995, SDZ-HDC-912, and YM 09151-2. 
     
     
         9 . A method according to  claim 2 , wherein said agent is a combination of dopamine with a dopamine D2-R antagonist. 
     
     
         10 . The method according to  claim 9 , wherein said agent is a combination of dopamine with clozapine. 
     
     
         11 . A method according to  claim 2 , wherein said agent is a combination of a dopamine D1-R agonist with a dopamine D2-R antagonist. 
     
     
         12 . The method according to  claim 11 , wherein said agent is a combination of SKF-38393 and clozapine. 
     
     
         13 . A method for treatment of cancer,
 said method comprising administering to a cancer patient an agent that down-regulates the suppressive activity of CD4 + CD25 +  regulatory T cells (Treg) on CD4 + CD25 −  effector T cells (Teff), wherein said agent is selected from the group consisting of:   (i) dopamine or a pharmaceutically acceptable salt thereof;   (ii) a dopamine precursor or a pharmaceutically acceptable salt thereof;   (iii) an agonist of the dopamine receptor type 1 family (D1-R agonist) or a pharmaceutically acceptable salt thereof;   (iv) an antagonist of the dopamine receptor type 2 family (D2-R antagonist) or a pharmaceutically acceptable salt thereof;   (v) a combination of (i) and (ii); and   (vi) a combination of (i), (ii) or (iii) with (iv).   
     
     
         14 . A method according to  claim 13  wherein said agent triggers tumor regression, stimulates the natural immunological defense against cancer, or inhibits cancer cell metastasis. 
     
     
         15 . The method according to  claim 14  wherein said tumor is a solid tumor. 
     
     
         16 . The method according to  claim 15  wherein said solid tumor is bladder, brain, breast, cervix, colon, esophagus, head and neck, larynx, liver, lung, melanoma, ovary, pancreas, prostate, renal, stomach, thyroid, uterus, vagina or vocal cord tumor. 
     
     
         17 . The method according to  claim 15  wherein said tumor is a non-solid malignant neoplasm. 
     
     
         18 . The method according to  claim 17  wherein said non-solid malignant neoplasma is a lymphoproliferative disorder selected from the group consisting of multiple myeloma, non-Hodgkin's lymphomas, and a lymphocytic leukemia, e.g., chronic lymphocytic leukemia (CLL), prolymphocytic leukemia (PLL), hairy cell leukemia, large granular lymphocyte leukemia and Waldenstrom's macroglubulinemia. 
     
     
         19 . A method according to  claim 13 , wherein said agent is dopamine or a pharmaceutically acceptable salt thereof. 
     
     
         20 . A method according to  claim 13 , wherein said agent is a combination of dopamine and the dopamine precursor levodopa, optionally in further combination with carbidopa. 
     
     
         21 . A method according to  claim 13 , wherein said agent is a dopamine D1-R agonist. 
     
     
         22 . The method according to  claim 21 , wherein said dopamine D1-R agonist is selected from the group consisting of A-77636, SKF-38393, SKF-77434, SKF-81297, SKF-82958, dihydrexidine and fenoldopam. 
     
     
         23 . A method according to  claim 13 , wherein said agent is a dopamine D2-R antagonist. 
     
     
         24 . The method according to  claim 23 , wherein said dopamine D2-R antagonist is selected from the group consisting of amisulpride, clozapine, domperidone, eticlopride, haloperidol, iloperidone, mazapertine, olanzapine, raclopride, remoxipride, risperidone, sertindole, spiperone, spiroperidol, sulpride, tropapride, zetidoline, CP-96345, LU111995, SDZ-HDC-912, and YM 09151-2. 
     
     
         25 . A method according to  claim 13 , wherein said agent is a combination of dopamine with a dopamine D2-R antagonist. 
     
     
         26 . The method according to  claim 25 , wherein said agent is a combination of dopamine with clozapine. 
     
     
         27 . A method according to  claim 13 , wherein said agent is a combination of a dopamine D1-R agonist with a dopamine D2-R antagonist. 
     
     
         28 . The method according to  claim 27 , wherein said agent is a combination of SKF-38393 and clozapine. 
     
     
         29 . A method according to  claim 1  for up-regulating the suppressive effect of Treg on Teff, said method comprising administering to an individual in need an agent that up-regulates the suppressive activity of Treg on Teff, wherein said agent is selected from the group consisting of:
 (i) an antagonist of the dopamine receptor type 1 family (D1-R antagonist) or a pharmaceutically acceptable salt thereof;   (ii) an agonist of the dopamine receptor type 2 family (D2-R agonist) or a pharmaceutically acceptable salt thereof; and   (iii) a combination of (i) and (ii).   
     
     
         30 . A method according to  claim 29 , wherein said agent is a dopamine D2-R agonist or a pharmaceutically acceptable salt thereof. 
     
     
         31 . A method according to  claim 30 , wherein said dopamine D2-R agonist is selected from the group consisting of bromocriptine, cabergoline, lisuride, pergolide, pramipexole, quinagolide, quinpirole, quinelorane, ropinirole, roxindole, talipexole, LY 171555, PPHT and TNPA. 
     
     
         32 . A method according to  claim 29 , wherein said agent is a dopamine D1-R antagonist or a pharmaceutically acceptable salt thereof. 
     
     
         33 . A method according to  claim 32 , wherein said dopamine D1-R antagonist is selected from the group consisting of SCH 23390, NNC 756, NNC 01-112 and CEE-03-310. 
     
     
         34 . A method according to  claim 29 , wherein said agent is a combination of a dopamine D2-R agonist and a dopamine D1-R antagonist. 
     
     
         35 . A method for treatment of an autoimmune disease, said method comprising administering to an individual suffering from an autoimmune disease an agent that up-regulates the suppressive activity of CD4 + CD25 + +regulatory T cells (Treg) on CD4 + CD25 −  effector T cells (Teff), wherein said agent is selected from the group consisting of (i) a dopamine D2-R agonist or a pharmaceutically acceptable salt thereof, a dopamine D1-R antagonist or a pharmaceutically acceptable salt thereof, and (iii) a combination of (i) and (ii). 
     
     
         36 . A method according to  claim 35 , wherein said agent is a dopamine D2-R agonist or a pharmaceutically acceptable salt thereof. 
     
     
         37 . A method according to  claim 36 , wherein said dopamine D2-R agonist is selected from the group consisting of bromocriptine, cabergoline, lisuride, pergolide, pramipexole, quinagolide, quinpirole, quinelorane, ropinirole, roxindole, talipexole, LY 171555, PPHT and TNPA. 
     
     
         38 . A method according to  claim 35 , wherein said agent is a dopamine D1-R antagonist or a pharmaceutically acceptable salt thereof. 
     
     
         39 . A method according to  claim 38 , wherein said dopamine D1-R antagonist is selected from the group consisting of SCH 23390, NNC 756, NNC 01-112 and CEE-03-310. 
     
     
         40 . A method according to  claim 35 , wherein said agent is a combination of a dopamine D2-R agonist and a dopamine D1-R antagonist. 
     
     
         41 . A method according to  claim 35 , wherein said autoimmune disease is Eaton-Lambert syndrome, Goodpasture's syndrome, Grave's disease, Guillain-Barré syndrome, autoimmune hemolytic anemia (AIHA), hepatitis, insulin-dependent diabetes mellitus (IDDM), systemic lupus erythematosus (SLE), multiple sclerosis (MS), myasthenia gravis, plexus disorders, e.g., acute brachial neuritis, polyglandular deficiency syndrome, primary biliary cirrhosis, rheumatoid arthritis, scleroderma, thrombocytopenia, thyroiditis, e.g., Hashimoto's disease, Sjögren's syndrome, allergic purpura, psoriasis, mixed connective tissue disease, polymyositis, dermatomyositis, vasculitis, polyarteritis nodosa, polymyalgia rheumatica, Wegener's granulomatosis, Reiter's syndrome, Behçet's syndrome, ankylosing spondylitis, pemphigus, bullous pemphigoid, dermatitis herpetiformis, Crohn's disease or uveitis. 
     
     
         42 . A method for controlling graft rejection in an individual undergoing tissue or organ transplantation which comprises administering to said individual an agent that up-regulates the suppressive activity of CD4 + CD25 +  regulatory T cells (Treg) on CD4 + CD25 −  effector T cells (Teff), wherein said agent is selected from the group consisting of (i) a dopamine D2-R agonist or a pharmaceutically acceptable salt thereof, a dopamine D1-R antagonist or a pharmaceutically acceptable salt thereof, and a combination of (i) and (ii). 
     
     
         43 . A method according to  claim 42 , wherein said agent is a dopamine D2-R agonist or a pharmaceutically acceptable salt thereof. 
     
     
         44 . A method according to  claim 43 , wherein said dopamine D2-R agonist is selected from the group consisting of bromocriptine, cabergoline, lisuride, pergolide, pramipexole, quinagolide, quinpirole, quinelorane, ropinirole, roxindole, talipexole, LY 171555, PPHT and TNPA. 
     
     
         45 . A method according to  claim 42 , wherein said agent is a dopamine D1-R antagonist or a pharmaceutically acceptable salt thereof. 
     
     
         46 . A method according to  claim 45 , wherein said dopamine D1-R antagonist is selected from the group consisting of SCH 23390, NNC 756, NNC 01-112 and CEE-03-310. 
     
     
         47 . A method according to  claim 42 , wherein said agent is a combination of a dopamine D2-R agonist and a dopamine D1-R antagonist. 
     
     
         48 - 122 . (canceled)